Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Prostaglandin E2 (PGE2) is the predominant eicosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.
Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying different pharmacological properties have been cloned. The EP4 subtype, a Gs-coupled receptor, stimulates cAMP production, and is distributed in a wide variety of tissue suggesting a major role in PGE2-mediated biological events.
Certain compounds of the present invention are generally disclosed in WO98/45268 and EP-A-1229034 as PDE4 inhibitors, in WO03/16254 as EP4 receptor antagonists, in WO00/64876 as PPAR ligand receptor binders, and in DE2500157 (U.S. Pat. No. 4,221,815) and DE2706977 (U.S. Pat. No. 4,181,658) as antidiabetic agents. WO00/20371 describes a family of PGE receptor antagonists differing from the present compounds by having an ortho-substitution pattern in the phenyl ring. WO01/57036 describes a series of nicotinamide PDE4 inhibitors.
The invention addresses the problem of providing EP4 receptor modulators (e.g., agonists and antagonists) which have improved EP4 receptor modulating activities (e.g., agonist or antagonist activities). In particular, it relates to the provision of EP4 receptor antagonists useful in therapy, particularly for the treatment of pain and inflammation conditions.